Pralatrexate is chemically, N-(4-{1-[(2,4-diaminopteridin-6-yl)methyl]but-3-yn-1-yl}benzoyl)-L-glutamic acid and has the structural formula:

Pralatrexate is an anti-cancer therapy. It is the first drug approved as a treatment for patients with relapsed or refractory peripheral T-cell lymphoma, or PTCL—a biologically diverse group of aggressive blood cancers. Pralatrexate is currently marketed under the trade name FOLOTYN® by Allos.
Pralatrexate was disclosed in U.S. Pat. Nos. 5,354,751 and 6,028,071.
According to the '071 patent, alpha-propargylhomoterephthalic acid dimethyl ester substantially free of homoterephthalic acid dimethyl ester was obtained by chromatographing alpha-propargylhomoterephthalic acid dimethyl ester residue obtained as part of the reaction between homoterephthalic acid dimethyl ester and propargyl bromide in the presence of tetrahydrofuran and sodium hydride on silica gel using cyclohexane and ethyl acetate (8:1) for the elution.
Pralatrexate was also reported in J. Med. Chem, 1993, 36, 2228-2231. According to the paper, pralatrexate is prepared by crystallizing pralatrexate diethyl ester in a mixture of 2-methoxyethanol and water in the presence of sodium hydroxide.
International patent application publication no. WO 2012/061469 ('469 patent) disclosed crystalline Form A, Form B and Form C of pralatrexate. According to the '469 patent, crystalline pralatrexate Form A can be prepared by crystallizing amorphous pralatrexate in formamide.
According to the '469 patent, crystalline pralatrexate Form B can be prepared by crystallizing amorphous pralatrexate in methanol or water.
According to the '469 patent, crystalline pralatrexate Form C can be prepared by crystallizing amorphous pralatrexate in a mixture of methanol and water.
Alpha-propargylhomoterephthalic acid dimethyl ester is a key staring material for the preparation of pralatrexate.
It has been found that the preparation of alpha-propargylhomoterephthalic acid dimethyl ester substantially free of homoterephthalic acid dimethyl ester by column isolation in the prior art. It is not commercially possible. The present invention makes now available a more efficient process for the purification of alpha-propargylhomoterephthalic acid dimethyl ester substantially free of homoterephthalic acid dimethyl ester by crystallization.
In particular, the present invention is directed to reduce or remove homoterephthalic acid dimethyl ester impurity from alpha-propargylhomoterephthalic acid dimethyl ester. Alpha-propargylhomoterephthalic acid dimethyl ester substantially free of homoterephthalic acid dimethyl ester used to proceed in the synthesis is very important in order avoid the sequential formation of homoterephthalic acid dimethyl ester during the transformation lading to the pralatrexate.
10-Propargyl-4-deoxy-4-amino-10-dezapteroic acid and 10-deazaaminopterin are potential impurities in pralatrexate formed by procedures described in the art.
The chemical formula of 10-propargyl-4-deoxy-4-amino-10-dezapteroic acid impurity may be represented as:

The chemical formula of 10-deazaaminopterin impurity may be represented as:

In particular, the present invention is directed to reduce or remove 10-propargyl-4-deoxy-4-amino-10-dezapteroic acid and 10-deazaaminopterin impurities from pralatrexate. The process of the invention may be used for obtaining pralatrexate in high purity with less than 0.1% of any individual impurities, in particular 10-propargyl-4-deoxy-4-amino-10-dezapteroic acid and 10-deazaaminopterin impurities.
Thus, one object of the present invention is to provide a novel process for the purification of alpha-propargylhomoterephthalic acid dimethyl ester substantially free of homoterephthalic acid dimethyl ester.
Another object of the present invention is to provide a novel process for the purification of pralatrexate.